title: Trimeric Tn antigen on syndecan 1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin α5β1 and matrix metalloproteinase 9.
abstract: We demonstrated previously that ppGalNAc-T13 (T13), identified as an up-regulated gene with increased metastasis in a DNA microarray, generated trimeric Tn (tTn) antigen (GalNAcα1-Ser/Thr)3 on Syndecan 1 in highly metastatic sublines of Lewis lung cancer. However, it is not known how tTn antigen regulates cancer metastasis. Here, we analyzed the roles of tTn antigen in cancer properties. tTn antigen on Syndecan 1 increased cell adhesion to fibronectin in an integrin-dependent manner. Furthermore, cell adhesion to fibronectin induced phosphorylation of focal adhesion kinase and paxillin in T13-transfectant cells. In the search of Syndecan 1-interacting molecules, it was demonstrated that tTn antigen-carrying Syndecan 1 interacted with integrin α5β1 and matrix metalloproteinase 9 and that these molecules shifted to a glycolipid-enriched microdomain/rafts along with increased metastatic potential in T13-transfectant cells. We also identified a tTn substitution site on Syndecan 1, demonstrating that tTn on Syndecan 1 is essential for the interaction with integrin α5β1 as well as for the reaction with mAb MLS128. These data suggest that high expression of the ppGalNAc-T13 gene generates tTn antigen on Syndecan 1 under reduced expression of GM1, leading to enhanced invasion and metastasis via the formation of a molecular complex consisting of integrin α5β1, Syndecan 1, and MMP-9 in the glycolipid-enriched microdomain/rafts.
authors.affiliation: Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Kaoru
authors.initials: K
authors.lastname: Akita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakada
authors.forename: Kazunori
authors.initials: K
authors.lastname: Hamamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsuchida
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okajima
authors.forename: Keiko
authors.initials: K
authors.lastname: Furukawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Urano
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051419:Paxillin / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D053668:Syndecan-1 / Q000378:metabolism*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D005353:Fibronectins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D039081:Integrin alpha5beta1; D020780:Matrix Metalloproteinase 9; D017350:N-Acetylgalactosaminyltransferases; D051419:Paxillin; D019000:Phosphotyrosine; D053668:Syndecan-1; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C040286:Tn antigen
keywords: Glycolipids; Glycosylation; Integrins; Lung Cancer; Metastasis; O-glycans; Tn Antigen